Anti-tubulin acting arylpyrrol, arylfuran and arylthiophene derivatives, method for the preparation thereof and for the use thereof as an antimitotic

Abstract

The invention relates to a compound represented by general formula (I) wherein Z represents N, O or S, and A represents a CH group, a nitrogen atom or an NL + group wherein L represents a straight-chained or branched C 1 -C 12 alkyl group. The invention also relates to a method for the preparation thereof and the use thereof as an antimitotic.

1. A compound represented by following formula I: 
       
         
           
           
               
               
           
         
       
       in which:
 Z represents N, O or S, 
 R1, R3, R4, R5 and R6 represent independently of one another an atom of hydrogen, an atom of fluorine, a C 1 -C 12  linear or branched alkyl group, a C 3 -C 12  cycloalkyl group, a C 2 -C 12  linear or branched alkenyl group, a CH 2 —B or CH 2 —CH 2 —B group in which B represents
 a phenyl group possibly substituted by one or more groups chosen among a C 1 -C 6  linear or branched alkyl group, a C 1 -C 6  linear or branched alkoxy group, a NH 2  group, a NO 2  group, a CN group, a COOH group, a C 1 -C 6  linear or branched CO 2 (alkyl) group, a CONH 2  group, a C 1 -C 6  linear or branched CONH(alkyl) group, a C 1 -C 6  linear or branched CON(alkyl) 2  group, a Cl atom, a Br atom, an I atom, an OH group, a COCF 3  group, an OSO 2 CF 3  group; 
 a naphthyl group; 
 an anthracenyl group; 
 a 9H-fluorenyl group possibly substituted at position 9 by one or two C 1 -C 12  linear or branched alkyl groups; 
 an anisyl group or a pyridinyl group; 
 
 R2 represents H, a C 1 -C 12  linear or branched alkyl group, a phenyl group, a benzyl group, a C 1 -C 6  linear or branched CO 2 (alkyl) group, a CO 2 (benzyl) group, a C 3 -C 6  linear or branched CO 2 (alkenyl) group, a tosyl group, a mesyl group, a 9-fluorenylmethoxycarbonyl (FMOC) group, a NH 2  group or a C 1 -C 6  linear or branched NH(alkyl) group, a C 1 -C 6  linear or branched N(alkyl) 2  group, NH tertiobutyloxycarbonyl, NHCO 2 CH 2  phenyl or R2 is absent when Z represents O or S; 
 X represents a C 1 -C 12  linear or branched alkyl group, a C 1 -C 12  linear or branched hydroxyalkyl group or a C 1 -C 12  linear or branched aminoalkyl group; 
 A represents a CH group, a nitrogen atom or a NL +  group in which L represents a C 1 -C 12  linear or branched alkyl group; 
 Y represents an atom of hydrogen, a C 1 -C 12  linear or branched alkyl group, a C 3 -C 12  cycloalkyl group, an OH group, a CN group, a N 3  group, a C 1 -C 12  linear or branched alkoxy group, a C 1 -C 12  linear or branched hydroxyalkyl group, a C 1 -C 12  linear or branched aminoalkyl group, N 2   + , a NZ1-NHZ2, NH—NZ1Z2 or NZ1Z2 group in which Z1 and Z2 represent independently of one another an atom of hydrogen, a C 1 -C 12  linear or branched alkyl group, a C 3 -C 12  cycloalkyl group, a phenyl group possibly substituted by one or more groups chosen among a C 1 -C 6  linear or branched alkyl group, a C 1 -C 6  linear or branched alkoxy group, a NH 2  group, a CN group, a COOH group, a C 1 -C 6  linear or branched CO 2 (alkyl) group, a CONH 2  group, a C 1 -C 6  linear or branched CONH(alkyl) group, a C 1 -C 6  linear or branched CON(alkyl) 2  group, a Cl atom, a Br atom, an I atom, an OH group, a COCF 3  group, an OSO 2 CF 3  group, a benzyl group, an anisyl group, a pyridinyl group, C(O)—W, C(S)—W or C(NH)—W in which
 W represents a C 1 -C 12  linear or branched alkyl group, a C 3 -C 12  cycloalkyl group, a C 1 -C 12  linear or branched alkoxy group, a C 1 -C 12  linear or branched alkylthio group or NQQ1 in which
 Q and Q1 represent independently of one another an atom of hydrogen, a C 1 -C 12  linear or branched alkyl group, a C 3 -C 12  cycloalkyl group or CH(M)CO 2 M1 in which
 M and M1 represent independently of one another a hydrogen atom, a C 1 -C 12  linear or branched alkyl group, a C 3 -C 12  cycloalkyl group, a C 2 -C 12  linear or branched alkenyl group, a phenyl group, a benzyl group, a CH 2 —B or CH 2 —CH 2 —B group in which B is as defined above, 
 
 
 
 
       with the exception of the following formulas: 
       
         
           
           
               
               
           
         
       
     
     
       2. A compound according to  claim 1  in which Z represents N. 
     
     
       3. A compound according to  claim 1  in which A represents the group CH. 
     
     
       4. A compound according to  claim 1  in which Y represents a NH 2  group or an atom of hydrogen. 
     
     
       5. A compound according to  claim 1  in which X represents a C 1 -C 12  linear or branched alkyl group. 
     
     
       6. A compound according to  claim 1  wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       7. A method of preparing compounds according to  claim 1  comprising the steps of:
 a) synthesizing a pyrrolylalkylcarbinole, furanylalkylcarbinole or thiophenylalkylcarbinole unit of following formula II: 
 
       
         
           
           
               
               
           
         
       
       in which Z, X, R1 and R4 are as defined in  claim 1  and GP represents a nitrogen protective group when Z represents N, or is absent when Z represents O or S, and
 b) functionalizing the pyrrolylalkylcarbinole, furanylalkylcarbinole, or thiophenylalkylcarbinole unit by introducing an aryl or heteroaryl unit at position 3 of the pyrrole, furan or thiophene ring. 
 
     
     
       8. A method according to  claim 7  wherein X represents (CH 2 ) 3 , and wherein step a) consists of the cyclodehydration of unsaturated β-γ aminoketones of following formula III: 
       
         
           
           
               
               
           
         
       
       in which Z, R1, R4 and GP are as defined in  claim 7  in order to obtain the product of following formula IV: 
       
         
           
           
               
               
           
         
       
       in which Z, R1, R4 and GP are as defined in  claim 7 , 
       followed by the introduction of the alcohol function by hydroboration-oxidation of the product of formula IV in order to obtain the product of formula II as defined in  claim 7 . 
     
     
       9. A method according to  claim 7  wherein R2, R3, R4, R5 and R6 represent an atom of hydrogen, Y represents a NH 2  group, A represents a CH group, X represents (CH 2 ) 3  and Z represents N, wherein step b) consists of:
 a palladium-catalyzed Suzuki-Miyaura cross-coupling of the compound of formula II, in which R4 represents an atom of hydrogen, X represents (CH 2 ) 3 , Z represents N and GP represents a nitrogen protective group, and of 2-triazene boronic acid in order to obtain a compound of following formula V: 
 
       
         
           
           
               
               
           
         
       
       in which GP represents a nitrogen protective group,
 deprotection of the triazene function in order to obtain the group of following formula VI: 
 
       
         
           
           
               
               
           
         
       
       in which GP represents a nitrogen protective group,
 specific deprotection of protective group GP in order to obtain the compound of formula I in which R2, R3, R4, R5 and R6 represent an atom of hydrogen, Y represents a NH 2  group, A represents a CH group, X represents (CH 2 ) 3 , and Z represents N. 
 
     
     
       10. A pharmaceutical composition comprising a compound according to  claim 1  or a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable excipient. 
     
     
       11. A compound of formula V: 
       
         
           
           
               
               
           
         
       
       in which GP represents a nitrogen protective group and R1 represents an atom of hydrogen, an atom of fluorine, a C 1 -C 12  linear or branched alkyl group, a C 3 -C 12  cycloalkyl group, a C 2 -C 12  linear or branched alkenyl group, a CH 2 —B or CH 2 —CH 2 —B group in which B represents a phenyl group possibly substituted by one or more groups chosen among a C 1 -C 6  linear or branched alkyl group, a C 1 -C 6  linear or branched alkoxy group, a NH 2  group, a NO 2  group, a CN group, a COOH group, a C 1 -C 6  linear or branched CO 2 (alkyl) group, a CONH 2  group, a C 1 -C 6  linear or branched CONH(alkyl) group, a C 1 -C 6  linear or branched CON(alkyl) 2  group, a Cl atom, a Br atom, an I atom, an OH group, a COCF 3  group, an OSO 2 CF 3  group; a naphthyl group; an anthracenyl group; a 9H-fluorenyl group possibly substituted at position 9 by one or two C 1 -C 12  linear or branched alkyl groups; an anisyl group or a pyridinyl group. 
     
     
       12. A compound of formula VI: 
       
         
           
           
               
               
           
         
       
       in which GP represents a nitrogen protective group and R1 represents an atom of hydrogen, an atom of fluorine, a C 1 -C 12  linear or branched alkyl group, a C 3 -C 12  cycloalkyl group, a C 2 -C 12  linear or branched alkenyl group, a CH 2 —B or CH 2 —CH 2 —B group in which B represents a phenyl group possibly substituted by one or more groups chosen among a C 1 -C 6  linear or branched alkyl group, a C 1 -C 6  linear or branched alkoxy group, a NH 2  group, a NO 2  group, a CN group, a COOH group, a C 1 -C 6  linear or branched CO 2 (alkyl) group, a CONH 2  group, a C 1 -C 6  linear or branched CONH(alkyl) group, a C 1 -C 6  linear or branched CON(alkyl) 2  group, a Cl atom, a Br atom, an I atom, an OH group, a COCF 3  group, an OSO 2 CF 3  group; a naphthyl group; an anthracenyl group; a 9H-fluorenyl group possibly substituted at position 9 by one or two C 1 -C 12  linear or branched alkyl groups; an anisyl group or a pyridinyl group.